Disubstituted desoxyalditols and process for their preparation



Patented Feb. 8, 1949 UNITED STATESPATENT ()FFICE 1 DISUBSTITUTED DESOXYALDITOLS AND PROCESS FOR THEIR- PREPARATION William Andrew Bonner, Hubbard Woods, and Charles D. Hurd, Evanston, 111., assignors to Corn Products Refining Company, New York, N. Y., a corporation of New Jersey No Drawing. Application December 31, 1945,

Serial No. 638,584

13 Claims. (01. 260-618) 1 This invention relates to a new series of organic chemical compounds, disubstituted desoxyalditols. More particularly it relates to 1-R-l-R'-1- desoxyalditols and their derivatives and to a process for their preparation.

The general formula for the compounds produced by the process of this invention may be represented as follows:

R specific substitution product thereof in the pres- 1 ence of anhydrous aluminum chloride as a 3 ca a ys HOHM The above reaction will be recognized as an H203 extension of the Friedel-Crafts reaction. While wherein R may be an alkyl, aryl, or aralkyl group and R is an aryl group; and n is a whole number, usually 3 or l.

A specific example of a l-R-l-R'-l-desoxyalditol produced by means of our invention is 1,1- diphenyl-l-desoxy-D-glucitol. This may be represented by the following structural formula:

applied to 1 -R-desoxyglycoses to produce l-R-l-R-1-desoxyalditols.

The reaction is believed to proceed according to the following illustrative equation involving the use, in this instance of a derivative of a l-R- l-desoxyglycose:

CH(C5H5)2 R R H on (2H na-Ar I A1013 1 HO H r H (CHOCOR)3 0 5am HOE); +4A10OR soon H more: H on cmooon OHOH wherein B. may be an alkyl, aryl, or aralkyl A specific example of a derivative of a group; Ar is an-aryl group; and R is an alkyl l-aJ-R'J-desoxyalditol obtained by the process group. The CHOH groups represented in the 0f t p t invention i L -d ph ld s v formula of the desoxyalditol actually do not ap- 2,3,4,5,6 p fiy t s y be pear until water has been added to isolate the represented by the o ow St u formula! desired products,as will be described later. They CH(CH5)2 are probably held by the aluminum chloride in H 0 Ac the following manner CHOAlCl2.

J In carrying out the present invention there H may be used as one of the reactants any l-R-l- H OAc desoxyglycose wherein B. may be an alkyl, aryl,

Further examples of l-R-l-Rl-l desoxyalditols produced by the process of the present invention desoxyglycose in the form of its acyl or similar, derivative. Such compounds and the processes for their preparation are the subjects of co-pending applications, Serial No. 638,583, filed Decemare ber 31, 1945, and Serial No. 638,585, filed Decem- Be a-l- -tol l-al ha 1 hen l- 1 -'desox -D- her 1945- i gtlucitgl y p p y y Examples of l-R-l-desoxyglycose derivatives Alpha-l-p-tolyl-beta l phenyl 1 desoxy-D which are suitable for purposes of the present glucitol F0 invention include 2,3,4,6-tetraacetyl-beta-D-glucosylbenzene, 2,3,4-triacetyl-beta-Dxylosyl-benzene, p- (2,3,4-triacety1-beta-D-xylosyl) toluene. Beta-l-phenyl-alpha 1 p-tolyl 1 'desoxy-D- p-(2,3,4,6-tetraacetyl-beta-D-glucosyl) toluene.

xylitol In carrying out the invention both substituted Alpha-l-phenyl-beta 1 p-tolyl 1 desoxy-D- and unsubstituted aromatic hydrocarbons may xylitol be used. Among the aromatic hydrocarbons 1 ,1 -dipheny1- l -desoXy-D-xylitol 1,1-di-p-tolyl-l-desoxy-D-xylitol such reaction is well known it has not been 40 or aralkyl group, or, preferably, any such 1- R- 1- thiophene and the like may be; used also.

' in the desired compounds.

lay r. 'ner. The. desired l Ral-Ri-1-desoxyalditol is which may be used in the process of the present invention are benzene, toluene, xylene, naphthalene. Compounds such as bromobenzene, anisole,

factany of the type of unsubstituted or substituted aromatic hydrocarbons whichare known to undergo the Friedel-Crafts reaction in general.

may also be used here. As the term hydrocarbon is used herein in the description and claims,.iti is' intended to refer to both substituted andunsubstituted hydrocarbons.

In carrying out the process of the present invention, the l-R-l-desoxyg-lycose: derivative is mixed with an excess of an aromatic hydrocarbon or substitution product thereof andto this mixture is added anhydrous aluminum chloride. This mixture is heated with stirring unti1 the reaction is complete. Hydrogen chloride gas is evolved copiously at first but subsides as the reaqtioncon-tin-ues. 'During, the reaction the aluminumchloride changes-from a powder tea light sum and eventually dissolves in the aromatic hydrocarbon whichdnadditionto being one ofthe reactants also serves as the medium for thereaction; After'thereaction'is complete, the mix.- ture is allowed to. cool and is then mixed with several volumes ofecold water. This treatment 7 j causesthe disappearance of the CHOAlClz complexes-and the appearance of the CHOl-Iigroups 'Iwo layers are formed, ail-aqueous layer and a non-aqueous These are separated in any suitable. manfound in the aqueous layer.; Thecatalyst, now in 1 the form of a soluble aluminum-salt is, alsorpres ent in thislayer.

The. aromatic ketonai. e.,-the AICOR in. the above equation together. with the excess, hydrocarbon. and higher boiling,

' ketone may be separated from the non-aqueous layer and purifiediby vacuum distillation or other suitable means The excess of aromatic hydrocarbon may be recovered in similar manner.

tarry products appear in the non-aqueouslayen The be effected by treating the same in conventional manner with a suitable solvent, such as 2-propanel. Deacetylation. of' the acetylated cornpoundwith methanol and sodiumin conventional manner yields the l-Ri-l- R l-dcsoxya'lditol in the methanc-l'solution. Removal of the methancl, as by distillation, leaves the l-R-l-R le desoxyalditol in solid form.

The process of the present invention may be carried out in any reaction vessel which is equippedwith means for agitation, means to allow for the escape of hydrogen chloride gas as it evolved, and also means to allow the reaction mixture" to be maintained at suitable reaction temperatures without the loss of the reactants.

The temperature at which the reaction ture should be heated will depend upon the ingredients therein, but in general should no exceed about 100 C. Generally, temperatures equivalent to those obtained byheatingthe reaction mixture'on a steam bath aresatisfactory.

Each of the reactants and also the catalyst should be in anhydrousform in order to carry out the reaction properly. The commercial grade of anhydrous aluminum chloride used for catalytic purposes is satisfactory for purposes of the pres ent invention. It is preferable-to add the hull: of the catalyst, if not all, at the beginning of the process.

The amount of aluminum chloride which is used as catalyst in the present invention will depend upon the form in which the l-R-l-desoxy- 'glocose isused. If, forexample, an acyl derivative the pyranose or furanose ring after the acyl Therecovery ofithe desired l--R-l-R'-l'-desoxyalditol from the aqueous layer is efiected by'fn'st adjusting the pH value of said layer to. aboutlil with an alkaline agent. This treatment pro- "duces' aluminum hydroxide which; is removedby filtration or the like The remaining filtrate is then treated fortheremoval or water therefrom,

as by distillation orthe like under diminished pressure. 'There' then: remains av dark colored sirup- In "addition to the desired product, this siruncontainsinorganic salts.

The l-R-l-R.eledesoxyalditolmayberecover d ,Ef m the. sirup b first. diss l n t time i as. small; an amount of-hot water as-will efiect such dissolution; Upon coolingof. theresultant solution crystals of the l-R- l.-.Rf.- L-desoxyalditol form and may be removed" and dried. inconventional manner. Further purification maybe. er-

fectedby recrystallization of-the. crystals. from ater- Alternately, the L-Ri-l-R l desoxyalditoll may be recovered from the sirup in the form .of'asuit.-

able derivative, such as the. acetate derivative. such case; the sirup is. -acetylated in known manner with aceticanhydride. Afterhydrolysis of the excess acetic. anhydrlde;v the acetylated productis recoveredjby extraction from theprqdgroups are'satisfiedi [The amount of catalyst necessary when an acyl derivative of a 1-R-l- .desoxyglycose is one of thereactants is 2a: 1 molecular equivalents, wherein :0 equals the nurrber of acyl groups. For example, if tetraacetyl- 'D-glucopyranosylbenzene were one of the reactants, nine molecular equivalents ofv aluminum chloride should be used for each mole of such desoxyglycose. Some substituent groups may require only one molecular. equivalentof. catalyst whileothersimay not require. any. In any case, however, itis necessary to provide sufficient' cat'- alyst so that the desiredzreactionmay be efiected. Considerably larger-amounts of aluminum chloride than above specified may be used also, although there is no particular advantage to be gained.

The time required for the reaction to take place will depend somewhat. upon the individual reactants present, but generally a period of heating under conditions as above described for 4 to 8 hours is satisfactory.

An; excess of the aromatic hydrocarbon should be used if the hydrocarbonisintendedto-serve as the reaction medium. Generally, the excess should be equal to at least about 60 times the amount of-"the hydrocarbon actually undergoing reaction. As already mentioned, the excesshy- -drocarbon may be recovered; Other solvents,

such as carbon disulfide, which are known to serve as reaction media for the Friedel-Crafts reaction may also be. 'usedhre for-such purpose.

The LR-l-desoxyglycose" should be .at' least partially, if not completely soluble in the aromatic hydrocarbon'with which reaction to be effected, or in a common solvent for both reactants which may serve as a reaction medium. The introduction of substituent groups, such as acyl, alkyl and the like, is an effective means of imparting the desired solubility characteristics to the desoxyglycose.

The amount of water added to decompose the aluminum complex should preferably be large enough to dissolve the desired dissubstituted desoxyalditol. To isolate the desired product readily, this should be dissolved in the water layer. Since, however, the desired product may in some instances be less soluble than in others, the water added should in all cases be added in amount sufiicient to efiect the desired dissolution.

Various alkaline agents may be used to adjust the pH value of the aforementioned water layer. Among the alkaline agents which are satisfactory are sodium hydroxide, sodium carbonate, potassium hydroxide, ammonium hydroxide and the like. I

As already mentioned the 1-R-1-R-1-desoxyalditol may be purified by recrystallizing the same from water. In some instances such compounds crystallize from water in the form of a hydrate. An example is 1,1-diphenyl-1-desoxy-D-glucitol hydrate.

1-R-1-R'-l-Desoxyalditols may also be isolated from the sirup obtained from the water layer in the form of derivatives other than the acetate, e. g., the propionate, butyrate, and the like. Purification of these may be efiected by the use of 2- propanol, methanol, ethanol and the like.

The following examples, which are intended as informative and typical only and not in a limiting sense, will further illustrate the invention, which is intended to be limited only in accordance with the scope of the appended claims.

Example 1.Preparation of LI-diphenyl-I- desomy D glucz'tol.-Tetraacetyl-beta-D-glucopyranosylbenzene (4.00 g.) was dissolved in dry benzene (150 ml.), and anhydrous aluminum chloride (13 g.) was added. The mixture was contained in a three-necked flask equipped with mercury seal, stirrer and reflux condenser, and.

was stirred under gentle reflux for six hours. After this, the mixture was cooled, poured into 500 ml. of cold water, stirred for one-half hour, and the layers separated and handled individually.

The benzene layer was washed several times with water, filtered, and dried over sodium sulfate. Removal of the solvent yielded 3.8 g. of an aromatic oil which was fractionated at atmospheric pressure through a small modified Claisen flask. The middle fraction (1.7 g., B. P. 198-202 1 C.) was identified as acetophenone.

The water layer, after being Washed with benzene and being combined with the washings of the original benzene layer, was neutralized with sodium hydroxide to a pH value of about 7.0 and filtered free of the precipitated aluminum hydroxide. The cake was washed twice by suspending it in water, boiling the suspension, and filtering the same, the washings being combined with the original filtrate. The combined filtrate and washings were distilled to dryness in vacuo, and the residue removed, air-dried and powdered. It was then returned to the same fiask, and acetylated by adding thereto acetic anhydride (250 ml.) and sodium acetate (20 g.) and heating the mixture with stirring on a steam bath for four hours. The acetylation mixture was cooled, poured into 400 ml. of cold Water, stirred for two hours, then extracted with ether. The ether solution was washed with water, then with dilute sodium hydroxide'solution, finally with water, and then dried. It was clarified b'y filtering it through decolorizing carbon. Removal of the solvent left 3.5 g. (66%) of crude, amber syrup. This was dissolved in hot 2-propanol and the solution allowed to cool. The crystalline product thereby obtained was identified as 1,l-diphenyl-1-desoxy-2,3,4,5,6-pentaacetyl-D glucitol, M. F. 93-95? C.

A one gram sample of the last mentioned compound was dissolved in methanol (20 ml.) and a small chip of sodium added. In several minutes the flask was filled with crystals, and after an hour these were collected, washed with methanol, and dried. The yield was 0.54 g. (88%) of 1,1-dipheny1-l-desoxy-D-glucitol. This compound upon purification from water formed a hydrate, the melting point thereof being 1554565 C. Oxidation of either above compound with alkaline permanganate produced p-benzoylbenzoic acid.

Example 2.Preparatzon 0 beta-1 -phenylalpha-1 -p-toZyZ-1 -desozry D gZucitol.-The procedure in this example was essentially the same as in Example 1. The amounts of reactants and catalyst were l-phenyl-l-desoxy2,3,l,6-tetraacetyl-beta- D-glucose grams 4.0

Toluene (dry) "milliliters" 130 Aluminum chloride (anhydrous) grams 13.0

The mixture was heated for 5 hours at 77-83 C. From the toluene layer after recovery of the toluene was isolated 3 g. of methyl p-tolyl ketone. Three parts of higher boiling tarry material remained. 1

The water layer was evaporated as before and acetylated. There was obtained 3.0 g. of an amber sirupy acetate. It was deacetylated directly by placing it in 150 m1. of methanol and adding thereto a little sodium. After minutes the methanol was removed by distillation thereof. The residue was dissolved in as small a volume of hot water as would dissolve the same. The solution was decolorizedwith decolorizing carbon and allowed to cool. This yielded 0.67 g. of crystals of beta-1-phenyl-alpha-l-p-tolyl-1-desoxy- D-glucitol hydrate. Upon repurification from water the melting point of the compoundwas found to be l671'70.5 C. and (00 in dioxane, 58.8 (conc. 0.400/ ml. of dioxane).

Example 3.-Prepa7ati0n of beta 1 p tolylalpha-1 -phenyZ-1 -deso:cy-D gZucitol.-The procedure used paralleled that of Example 1. The amounts of the compounds used were as follows:

p- (2,3,4,6-tetraacetylbeta-D-glucopyran0syl) toluene gram 1 Benzene (dry) mi1liliters 40 Aluminum chloride (anhydrous) .grams 3.0

There was obtained 0.52 g. of sirupy pentaacetate from the water layer. Deacetylation in the manner described in Example 1 resulted in 0.21 g. (27%) of beta-l-p-tolyl-alpha-l-phenyll-desoxy-D-glucitol. This crystallized from water as the hydrate. After the hydrate was recrystallized from water three times, the melting point of the hydrate was found to be 1515-4535" C. and (00 in dioxane was found to be 55.8 (conc. 0.305 g./ 100 ml. of dioxane).

Example 4.-Preparation of 1,1 diphenyl -1- clesoazy-D-acylitol.--The procedure used was essentially the same as that described in Example 1.

phenyl-l-desoxy D glucitol. from water, in-the form of long needle-shaped crystals, which. were determined to be the anhydrousform, M. B. 168.5 C.

amounts; of, the cqnlpoundg used. were as iollawsr 'Ifiaoetyi-bfifiy y osylbenzene Y "gram" 1.0 1 3 18 -d-ry .11 1 40 Aluminum chloride ianhydrous) grains 3.55

Therefluxpericd wast hours.

There was obtained from the water layer 0.42

3.2% of clear, amber sirup. This. on acetyla- I tion followed by deacetylation resulted. in 1,1,-di-

This crystallized Example 5.-Prepamtion of beta, 1 -'p toZyZ- clpha l-phenylel-desoxyD-xylitl.-One g. of

triaeetyl -betarD-xylopyrancsyltoluene, 45 .ml. of

dry-benzene, and 3.55. g. of anhydrous aluminum sents a radicalselected from the group consisting of-alkyl, aryl and aryl group.

2;. The process o f preparing disubstituted e cxyalditcls h ch. om r ses Qn-ta t n r und r substa t ally n y r us ondit c sa dat e evataralkyl and R. represents an dLtemuera-tu netexc g 1 0 i. l -1- 'desoxyglycose,'wherein. R represents a radical selected trom the group consisting of alkyl, aryl and aralkyl, and anaromatic hydrocarbon in the .presence of sufficient anhydrous aluminum chl0-,

ride-t0 efiect the-desired reaction. 7 j

3. The process of preparing disubstituted desoxyalditols which comprises contacting, un-" der; substantiallyanhydrous conditions and at elevated,- temperature. not exceeding l00, C;, an acylderivative o f'a l-R-l-desoxyglycose, whereinR represents a. radical selected from the group consisting; of alkyl, aryl and aralkyl, and an aromatic hydrocarbon in the presenceof atleast about 2:1: +1 m 0l ecul ar equivalent of anhydrous aluminum chloride with respect to saidacyl derivatir wher in: a; equa s; thenumber' of acid er ues'i sa d act derivatii i 4. The; process according; to claim 2 wherein thert me t ontactranges from abqute to 'bqu 8 hours. 77 r 'llhe; process acc rding o. laim-,-3 wher i the time of contact ranges fromabout 4 to about hours. r

reaction, under substantially anhydrous conditions, between tetraacetyl-De lucopyranosylbenzene and. benzene in the presence of at least 9 molecular equivalents: of aluminum chloride, baseclupon the Weight of thGtEtl'3fiC6tY1-Dy-Ehlcopyranosylbenzene said reaction being effected at elevated temperature, not exceeding; about 100. I C. and thetime for efiecting said. reaction 7 ranging from about 4 to about 8 hours.

. time for effecting 12. The process which comprises: reflecting the reaction, under substantially anhydrousconditicns, between tetraacetyle-Diglucopyrancsylbene zene; and toluene inthe; presence of at least 9 molecular equivalents of aluminum chloride, based upon'the; weight of thetetraacetyl Deglucopyranosylbenzene; said reaction being effected t e a d. temperaturanct xc eding abo 10 C. and the time efiectin "s from about 4 to about8,houiis.

l3. The process which comprises efiectingx the reaction, under substantiallyanhydrous conditions, between triacetyl D-xylopyranosylbenzene and benzene in the presence of at least-9 molecular equivalents. of aluminum chloride based upon the weight of the triacetyl-Dexylopyranosylbenzene; d. reacticn: beine-efi cted t elevat d temperature, not exceeding about. C. and the said reaction ranging from about itcabout8 hoursQ w CHARLES D. HURD.

' 1N0 r ierenc s cit d- -.d ailman-rang n 

